The Pima Indians of Arizona have one of the highest reported prevalence of obesity and diabetes mellitus in the world. Whether body weight gain and diabetes mellitus is the consequence of a thrifty gene is not yet known. Since 1984, the different components of daily energy expenditure (sleeping metabolic rate, energy cost of arousal, thermic effect of food, and the energy cost of physical activity) have been measured in both Pima Indians and Caucasians using a human respiratory chamber. The cross-sectional and longitudinal results to date have shown that: 1) the rate of resting or 24-hour energy metabolism is a familial trait independent of individual differences in body size, age, and sex, 2) the level of physical activity, as well as the fuel mix which is oxidized over 24 hours, are also familial traits. These results support an important genetic factor in the determination of an individual's metabolic rate or fuel utilization. 3) thermic effect of food is independent of the degree of obesity and a low thermic effect of food is not a predictor of weight gain, 4) carbohydrate and protein stores are closely regulated by adjustment of oxidation to intake, whereas fat is almost exclusively used or stored in response to day-to-day fluctuation in energy balance, 5) a low resting or 24-hour energy expenditure is a risk factor for body weight gain, 6) even though peripubertal children from obese parents had similar responses to overfeeding when compared to offspring from lean parents, offspring of obese parents were more receptive to overfeeding. We are continuing to use the respiratory chamber to investigate the short-term energy metabolism in response to over- and underfeeding in adults and, in conjunction with the use of doubly-labeled water, are planning to measure the energy cost of physical activity in free-living conditions. Also, we are presently investigating the effect of age and physical fitness on energy expenditure.